Delebarre Mathilde, Gonzales Fanny, Behal Hélène, Tiphaine Aude, Sudour-Bonnange Hélène, Lutun Anne, Abbou Samuel, Pertuisel Sophie, Thouvenin-Doulet Sandrine, Pellier Isabelle, Mansuy Ludovic, Piguet Christophe, Paillard Catherine, Blanc Laurence, Thebaud Estelle, Plantaz Dominique, Blouin Pascale, Schneider Pascale, Guillaumat Cécile, Simon Pauline, Domenech Carine, Pacquement Hélène, Le Meignen Marion, Pluchart Claire, Vérite Cécile, Plat Geneviève, Martinot Alain, Duhamel Alain, Dubos François
ULR 2694-METRICS: Évaluation des technologies de santé et des pratiques médicales, Université de Lille, Lille, France; Paediatric Emergency Unit & Infectious Diseases, Lille, France; Paediatric Haematology Unit, CHU Lille, Lille, France.
Paediatric Haematology Unit, CHU Lille, Lille, France.
Lancet Child Adolesc Health. 2022 Apr;6(4):260-268. doi: 10.1016/S2352-4642(21)00337-0. Epub 2021 Dec 3.
In 2017, international guidelines proposed new management of febrile neutropenia in children with cancer, adapted to the risk of severe infection by clinical decision rules (CDRs). Until now, none of the proposed CDRs has performed well enough in high-income countries for use in clinical practice. Our study aimed to build and validate a new CDR (DISCERN-FN) to predict the risk of severe infection in children with febrile neutropenia.
We did two prospective studies. First, a prospective derivation study included all episodes of febrile neutropenia in children (aged <18 years) with a cancer diagnosis and receiving treatment for it who were admitted for an episode of febrile neutropenia, excluding patients already treated with antibiotics for this episode, febrile neutropenia not induced by chemotherapy, those receiving palliative care, and those with a stem cell allograft for less than 1 year, from April 1, 2007, to Dec 31, 2011 from two paediatric cancer centres in France. We collected the children's medical history, and clinical and laboratory data, and analysed their associations with severe infection. Sipina software was used to derive the CDR as a decision tree. Second, a prospective, national, external validation study was done in 23 centres from Jan 1, 2012, to May 31, 2016. The primary outcome was severe infection, defined by bacteraemia, a positive bacterial culture from a usually sterile site, a local infection with a high potential for extension, or an invasive fungal infection. The CDR was applied a posteriori to all episodes to evaluate its sensitivity, specificity, and negative likelihood ratio.
The derivation set included 539 febrile neutropenia episodes (270 episodes in patients with blood cancer [median age 7·5 years, IQR 3·7-11·2; 158 (59 %) boys and 112 (41%) girls] and 269 in patients with solid tumours [median age 6·6 years, IQR 2·9-14·2; 140 (52 %) boys and 129 (48%) girls]). Significant variables introduced into the decision tree were cancer type (solid tumour vs blood cancer), age, high-risk chemotherapy, level of fever, C-reactive protein concentration (at 24-48 h after admission), and leucocyte and platelet counts and procalcitonin (at admission and at 24-48 h after admission). For the derivation set, the CDR sensitivity was 98% (95% CI 93-100), its specificity 56% (51-61), and the negative likelihood ratio 0·04 (0·01-0·15). 1806 febrile neutropenia episodes were analysed in the validation set (mean age 8·1 years [SD 4·8], 1014 (56%) boys and 792 (44%) girls), of which 332 (18%, 95% CI 17-20) were linked with severe infection. For the validation set, the CDR had a sensitivity of 95% (95% CI 91-97), a specificity of 38% (36-41), and a negative likelihood ratio of 0·13 (0·08-0·21). Our CDR reduced the risk of severe infection to a post-test probability of 0·8% (95% CI 0·2-2·9) in the derivation set and 2·4% (1·5-3·9) in the validation set. The validation study is registered at ClinicalTrials.gov, NCT03434795.
The use of our CDR substantially reduced the risk of severe infection after testing in both the derivation and validation groups, which suggests that this CDR would improve clinical practice enough to be introduced in appropriate settings.
Ligue Nationale Contre le Cancer.
2017年，国际指南提出了针对癌症患儿发热性中性粒细胞减少症的新管理方法，通过临床决策规则（CDR）来适应严重感染风险。到目前为止，在高收入国家中，所提出的任何CDR在临床实践中的表现都不够理想。我们的研究旨在构建并验证一种新的CDR（DISCERN-FN），以预测发热性中性粒细胞减少症患儿发生严重感染的风险。
我们进行了两项前瞻性研究。首先，一项前瞻性推导研究纳入了所有年龄小于18岁、诊断为癌症并正在接受治疗的发热性中性粒细胞减少症患儿，这些患儿因发热性中性粒细胞减少症发作而入院，排除已针对此次发作使用抗生素治疗的患者、非化疗诱导的发热性中性粒细胞减少症患者、接受姑息治疗的患者以及接受干细胞同种异体移植少于1年的患者，研究对象来自法国两个儿科癌症中心，时间为2007年4月1日至2011年12月31日。我们收集了患儿的病史、临床和实验室数据，并分析了它们与严重感染的关联。使用Sipina软件将CDR推导为决策树。其次，在2012年1月1日至2016年5月31日期间，在23个中心进行了一项前瞻性全国外部验证研究。主要结局是严重感染，定义为菌血症、通常无菌部位的细菌培养阳性、具有高度扩散潜力的局部感染或侵袭性真菌感染。将CDR事后应用于所有发作，以评估其敏感性、特异性和阴性似然比。
推导组包括539例发热性中性粒细胞减少症发作（血液系统癌症患者270例发作[中位年龄7.5岁，IQR 3.7 - 11.2；158例（59%）为男孩，112例（41%）为女孩]，实体瘤患者269例发作[中位年龄6.6岁，IQR 2.9 - 14.2；140例（52%）为男孩，129例（48%）为女孩]）。引入决策树的显著变量包括癌症类型（实体瘤与血液系统癌症）、年龄、高风险化疗、发热程度、C反应蛋白浓度（入院后24 - 48小时）以及白细胞和血小板计数及降钙素原（入院时和入院后24 - 48小时）。对于推导组，CDR的敏感性为98%（95%CI 93 - 100），特异性为56%（51 - 61），阴性似然比为0.04（0.01 - 0.15）。验证组分析了1806例发热性中性粒细胞减少症发作（平均年龄8.1岁[标准差4.8]，1014例（56%）为男孩，792例（44%）为女孩），其中332例（18%，95%CI 17 - 20）与严重感染相关。对于验证组，CDR的敏感性为95%（95%CI 91 - 97），特异性为38%（36 - 41），阴性似然比为0.13（0.08 - 0.21）。我们的CDR在推导组中将严重感染风险降低至测试后概率为0.8%（95%CI 0.2 - 2.9），在验证组中为2.4%（1.5 - 3.9）。验证研究已在ClinicalTrials.gov注册，编号为NCT03434795。
在推导组和验证组中进行测试后，使用我们的CDR可大幅降低严重感染风险，这表明该CDR将足以改善临床实践，可在适当环境中引入。
法国国家抗癌联盟。
